Ribonucleases are primordial enzymes that play important roles in nature. They mediate several essential biological activities, namely, regulation of cell proliferation, maturation, differentiation, and cell death. Therefore, they are ideal candidates for the development of therapeutics for cancer and other life-threatening diseases (including HIV, and autoimmune diseases), that require anti-proliferative and apoptotic properties.

ONCONASE® (ranpirnase), Alfacell's flagship product, is a novel amphibian ribonuclease unique among the superfamily of pancreatic ribonuclease. ONCONASE® has demonstrated on a molecular level to re-regulate the unregulated growth and proliferation of cancer cells, as well as inhibit virus replication (e.g., HIV) in infected cells. Unlike most cancer drugs that attack all cells regardless of their phenotype (malignant vs. normal) and produce a variety of severe toxicities, ONCONASE® is not an indiscriminate cytotoxic agent. ONCONASE® affects primarily malignant exponentially growing cells, and its activity is mediated through elegant molecular mechanisms.

One of the most characteristic features of cancer cells is their genetic instability and ability to develop various forms of resistance to treatment - especially to single anti-cancer agents that target the same or similar molecular targets. Tumor cells possess several redundant growth signal transduction pathways interconnected at several levels. Thus, tumor cells can quickly develop multiple "bypass" or alternative pathways of effective pro-growth and anti-apoptosis signaling that defeat the long-term therapeutic efficacy of most anti-cancer drugs. However, using combinations of agents with different mechanisms of action can minimize the development of drug resistance. By affecting multiple intracellular sites, ONCONASE® influences several functions in the tumor cell simultaneously. As such, ONCONASE® has been shown to overcome multiple drug resistance and to enhance the cytotoxicity of a variety of anti-cancer agents.

Our preclinical and clinical data indicates that ONCONASE® and our family of novel ribonuceases can be used in a variety of cancer treatment modalities, including:

• Monotherapy
• Combination with one or more anti-cancer agents
• Payload for a chemical conjugate
• Fusion products (internalizing antibodies, growth factors, cytokines)

The concept of targeting potent toxins as effector molecules to kill cancer or other specifically targeted cells has been extensively evaluated over the last 2 decades. Several immunotoxins containing bacterial and plant toxins, other biotoxins, have been evaluated in human clinical trials. Efficacy has always been limited due to the high incidence of immunogenicity and other intolerable toxicities, including death. Conjugation of ranpirnase to targeting ligands appears to eliminate this safety problem.

Proof-of-concept studies have been conducted by the NCI and published.

This Figure illustrates the relative potency of various toxins as measured by inhibition of protein synthesis in Xenopus laevis oocyte model. Ricin A and Diphtheria toxin are among the most lethal poisons known to man. Ranpirnase was determined to be the most potent in this experimental model.

Relative potencies of various toxins measured as a percent of inhibition of protein synthesis. Ranpirnase was found to be the most potent as compared to Ricin A, Diphtheria toxin, a Sarcin, and RNase A.

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